What are the root causes of Rheumatoid Arthritis (RA)?

From the Guidelines

The root causes of Rheumatoid Arthritis (RA) are primarily driven by a combination of genetic predisposition, environmental factors, and autoimmune responses, with certain HLA genes, such as HLA-DRB1*1402, and serum autoantibodies like anti-citrullinated protein antibodies (ACPA) playing crucial roles. The development of RA is influenced by various factors, including:

• Genetic predisposition, with certain HLA genes, such as HLA-DRB1, increasing susceptibility to RA 1
• Environmental triggers, such as smoking and infections, which can increase the risk of developing RA, especially in genetically predisposed individuals
• Autoimmune responses, where the body's immune system mistakenly attacks the synovial membrane lining the joints, triggered by the presence of serum autoantibodies like ACPA and rheumatoid factor (RF) 1
• Geographical and ethnic factors, with certain populations, such as Indigenous North Americans, exhibiting a higher genetic risk of RA due to the presence of specific HLA genes, like HLA-DRB1*1402 1
• Hormonal factors, which may contribute to the higher incidence of RA in women compared to men The presence of ACPA and other serum biomarkers can enable the identification of important subpopulations at risk of developing RA, particularly in first-degree relatives (FDRs) of people with RA and in genetically predisposed indigenous populations 1. Overall, the complex interplay between genetic, environmental, and autoimmune factors contributes to the development of RA, with genetic predisposition and autoimmune responses being the primary drivers of the disease.

From the Research

Root Causes of Rheumatoid Arthritis (RA)

The root causes of Rheumatoid Arthritis (RA) are complex and multifactorial, involving a combination of genetic and environmental factors. Some of the key factors include:

• Genetic factors:
  • HLA-DRB1 alleles are considered the main RA gene, but they are neither necessary nor sufficient to cause the development of RA in a given individual 2
  • Other genes such as TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22 have also been associated with an increased risk of RA 2
  • More than 100 RA susceptibility loci have been identified by genome-wide association studies (GWAS) and GWAS meta-analyses 3
• Environmental factors:
  • Smoking is a well-known environmental risk factor for RA, and it interacts with HLA-DR shared epitope genes to increase the risk of RA 4
  • Exposure to tobacco smoke has been associated with an increased risk of RA 5
  • Mucosal inflammation and microbial factors may also contribute to the development of RA 5
  • Early life factors such as maternal smoking during pregnancy, higher birth weight, and breastfeeding may also influence the risk of RA 6
• Other factors:
  • Female sex and a family history of RA are also associated with an increased risk of RA 5
  • The "shared epitope" genetic factor has been associated with an increased risk of RA 5

Genetic and Environmental Interactions

The interaction between genetic and environmental factors is thought to trigger immunologic events that eventually result in the clinical signs of arthritis 4. Understanding the exact role and timing of action of risk factors for RA is important for the development of effective preventive interventions 5.

Preclinical RA

There is evidence of a "preclinical" period of RA, characterized by local or systemic autoimmunity as measured by autoantibodies and other biomarkers prior to the development of clinically apparent synovitis 5. This suggests that the risk factors for RA are acting long before the first clinical evidence of the disease.